Pipetting device, modular pipetting unit, pipetting system and method for pipetting of fluid samples

ABSTRACT

A pipetting device having a modular pipetting unit including a pipetting tip for pipetting of fluid samples and a pump conduit for transferring a negative or positive pressure to the pipetting tip is disclosed. The pipetting tip and a portion of the pump conduit adjoining the pipetting tip mutually define a fluid sample conduit for receiving the fluid samples. The modular pipetting unit is detachably attached to an automated positioning device for positioning the modular pipetting unit. A system and method for pipetting of fluid samples using such a pipetting device are also disclosed wherein pipetting of the fluid samples is performed in such a manner that each pipetted fluid sample volume is smaller than a volume of the fluid sample conduit.

TECHNICAL FIELD

Embodiments of the present invention relate generally to automatedhandling of fluid samples and more particularly to a pipetting device, amodular pipetting unit, a pipetting system and a method for theautomated pipetting of fluid samples.

BACKGROUND

In consideration of the fact that there is an ongoing increase in(bio-)chemical and genetic analyses and assays, a strong demand for theautomated pipetting of fluids can be observed.

In recent years, many efforts have been made to develop new automatedpipetting devices most often provided with a plurality of pipettesenabling plural pipetting operations in parallel. Each of the pipettesis provided with a pipetting tip connected to a pump by means of a pumpconduit to transfer pump-generated negative or positive pressure to thepipetting tip for aspirating and dispensing of fluids, respectively.Conventionally, plunger pumps are being used for pipetting operationswhich advantageously allow for high-precision pipetting of fluids,however, typically are heavy in weight and thus may not be movedtogether with the pipetting tips due to an undesired strong increase ininertia. This especially applies to the case of independently operablepipettes requiring each pipette to be provided with a separate plungerpump.

Hence, plunger pumps are kept stationary when moving the pipetting tipsand, for instance, are fixed to a base-plate, which, however, enlargesthe overall dimensions of the automated pipetting device and hinders anintegrated and compact design of the pipettes. Moreover, lengthy pumpconduits in-between pump and pipetting tips aggravate variousmaintenance tasks (e.g. leakage detection) and disadvantageously enlargedead volumes which, however, essentially influence precision ofpipetting operations.

US-patent application No. 2008/0019878 A1 to Trump discloses apositioning device for pipettes in which a profiled rail accommodates apump drive. While such positioning device makes the pump drive anintegrated part of the profiled rail, such construction, however,disadvantageously requires the positioning device to be newly adjustedeach time the pump drive has to be serviced. For that reason,maintenance of the pump drive due to failures will result in undesirablyhigh costs. Furthermore, irrespective of the fact that plural pipettesrequire a rather complex construction, the positioning device may not bereadily adapted to varying demands.

SUMMARY

It is against the above background that that present invention in oneembodiment relates to a pipetting device that is flexible in use andallows for an integrated and compact design of independent pipettes. Thepipetting device comprises at least one modular pipetting unit whichincludes a pipetting tip for pipetting of fluid samples and a pumpconduit for transferring a negative or positive pressure to thepipetting tip, wherein the pipetting tip and at least a portion of thepump conduit adjoining the pipetting tip mutually define a fluid sampleconduit for receiving the fluid samples, and wherein the modularpipetting unit being detachably attached to an automated positioningdevice for positioning the modular pipetting unit. The present inventionin other embodiments relates to such a modular pipetting unit and amethod for pipetting of fluid samples using such a pipetting device arealso disclosed. The pipetting of the fluid samples is performed in suchthat each pipetted fluid sample volume is smaller than a volume of thefluid sample conduit. The present invention in a further embodimentrelates to a pipetting system, comprising at least one pipetting unitincluding a pipetting tip for pipetting fluid samples and a pump conduitfor transferring a negative or positive pressure to the pipetting tip,wherein the pipetting tip and at least a portion of the pump conduitadjoining the pipetting tip mutually define a fluid sample conduit forreceiving the fluid samples; an automated positioning device forpositioning of the at least one pipetting unit; and a controller forcontrolling of pipetting of the fluid samples, configured to controlpipetting of fluids such that each pipetted volume of the fluid samplesis smaller than a volume of the fluid sample conduit.

In one preferred embodiment, a pipetting device is disclosed andcomprises an automated positioning device; and at least one modularpipetting unit which includes a pipetting tip for pipetting of fluidsamples and a pump conduit for transferring a negative or positivepressure to the pipetting tip. The pipetting tip and at least a portionof the pump conduit adjoining the pipetting tip mutually define a fluidsample conduit receiving the fluid samples. The modular pipetting unitis detachably attached to the automated positioning device whichpositions the modular pipetting unit.

In another preferred embodiment, a modular pipetting unit is disclosedand comprises at least one pipetting tip for pipetting of fluid samples;and a pump conduit for transferring a negative or positive pressure tothe pipetting tip. The pipetting tip and at least a portion of the pumpconduit adjoining the pipetting tip mutually define a fluid sampleconduit for accommodating the fluid samples.

In still another preferred embodiment, a method for pipetting of fluidsamples is disclosed. The method comprises providing a pipetting devicewhich comprises at least one pipetting unit provided with a pipettingtip for pipetting of fluid samples and a pump conduit, the pipetting tipand at least a portion of the pump conduit adjoining the pipetting tipmutually define a fluid sample conduit, and the pump conduit being atleast partly filled with a liquid system fluid; and moving the liquidsystem fluid in the pump conduit to transfer a negative or positivepressure to the pipetting tip via the fluid sample conduit to pipettethe fluid samples, wherein a pipetted fluid sample volume is smallerthan a volume of the fluid sample conduit.

In yet another preferred embodiment, a pipetting system is disclosed andcomprises at least one pipetting unit which includes a pipetting tip forpipetting fluid samples and a pump conduit for transferring a negativeor positive pressure to the pipetting tip, wherein the pipetting tip andat least a portion of the pump conduit adjoining the pipetting tipmutually define a fluid sample conduit for receiving the fluid samples;an automated positioning device for positioning of the at least onepipetting unit; and a controller for controlling pipetting of the fluidsamples such that each pipetted volume of the fluid samples is smallerthan a volume of the fluid sample conduit.

Other and further embodiments, features and advantages of the inventionwill appear more fully from the accompanying drawings, the followingdetailed description, and the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings like designations denote like or similar elements, andin which:

FIG. 1 is a schematic perspective view of an exemplary embodiment of apipetting module according to the invention;

FIG. 2 is a schematic perspective view of an exemplary embodiment of apipetting device of the invention including plural pipetting modules asillustrated in FIG. 1;

FIG. 3 is a schematic perspective view of a variant of the pipettingdevice of FIG. 2, wherein each pipetting module accommodates amicro-gearwheel pump;

FIG. 4 is a schematic diagram of a pipetting channel of the pipettingdevice of FIG. 2 or 3 connected to a liquid system fluid reservoir; and

FIGS. 5A-5D are schematic cross-sectional views illustrating operationof a micro-gearwheel pump.

REFERENCE LIST

-   1 Pipetting device-   2 Pipetting module-   3 Pipetting tip-   4 Pump conduit-   5 First portion of pump conduit-   6 Guiding face-   7 Cartridge-   8 Inner wall-   9 Outer surface-   10 Fluidic connector-   11 First curved tubing portion-   12 Cavity-   13 Sensor arrangement-   14 Electric connector-   15 transfer head-   16 Horizontal guiding rail-   17 Guiding chain-   18 Gearwheel pump-   19 Vertical guiding rail-   20 Sliding carriage-   21 Chain link-   22 Longer tubing portion-   23 Shorter tubing portion-   24 Curved tubing portion-   25 Fluid sample conduit-   26 Positioning device-   27 Pipetting channel-   28 Optical flow sensor-   29 Reservoir tubing-   30 Pressure sensor-   31 System fluid valve-   32 System fluid reservoir-   33 DC electric motor-   34 First inlet/outlet port-   35 Second inlet/outlet port-   36 Inner rotor-   37 Outer rotor-   38 Inner rotor rotation axis-   39 Outer rotor rotation axis-   40 Pressure chamber-   41 Controller

DETAILED DESCRIPTION

According to an embodiment of the invention, a pipetting device forpipetting of fluid samples is provided. The pipetting device comprisesat least one modular pipetting unit, in the following referred to as“pipetting module”, including a pipetting tip for aspirating anddispensing (i.e. pipetting) of fluids and a pump conduit fortransferring a pump-generated negative or positive pressure to thepipetting tip. The pipetting tip and at least a portion of the pumpconduit adjoining the pipetting tip mutually define a duct, in thefollowing referred to as “fluid sample conduit”, which is used forreceiving fluids aspirated through the pipetting tip. The pump conduitmay, e.g., be embodied as wound (e.g. flexible) entity including one ormore windings. Such pump conduit allows for a wide range of volumes bepipetted according to the specific demands of the user. Moreover, thepump conduit can be readily replaced in particular in case ofcontamination of the pump conduit. Each winding may, e.g., includelinearly extending portions connected by curved portions. Specifically,the pump conduit may include plural windings, each of which includinglinearly extending portions connected by curved portions, wherein thepipetting tip is being connected to a linearly extending portion, i.e.end portion of the pump conduit. In the latter case, the fluid sampleconduit may, e.g., be composed of the pipetting tip and the linearlyextending portion immediately connected therewith. The pipetting devicefurther includes an automated positioning device for positioning of theat least one pipetting module with the pipetting module being detachablyattached to the automated positioning device. Accordingly, the pipettingmodule is being configured as a detachably mounted structural entitywhich can be fixed to or removed from the positioning device as desired.

The positioning device may, for instance, be developed as robot arm or,more preferably, as positioning device comprising components of movementin two directions of travel in a plane and a third direction of travelvertical thereto such as a beam translation system. In the latter case,the pipetting module preferably is detachably fixed to a transfer headwhich is moveable towards and away from the plane. Detachably fixed inthis context means that the pipetting module can be fixed to anddetached from the positioning device without giving up the unity of themodule. Preferably the pipetting module can be fixed to the positioningdevice and detached from it without disassembling or dismantling thepipetting module. This can be achieved by e.g. fixing the pipettingmodule with screws to the positioning device. It has to be understoodthat the pipetting module comprises the components as described furtherbelow herein.

The pipetting device according to an embodiment of the invention mayfurther include a controller for controlling of pipetting operations.The controller may, e.g., be embodied as a programmable logic controllerrunning a machine-readable program provided with instructions to performoperations in accordance with a predetermined process operation plan forpipetting of fluids.

Due to the modular construction of the at least one pipetting moduleenabling each of the pipetting modules to be fixed to and removed fromthe positioning device, respectively, the pipetting device of thepresent invention can be readily adapted to various needs as desired. Inthat, as defective pipetting modules may be easily replaced, maintenanceof the pipetting device in case of failures is considerably simplifiedresulting in reduced downtime and maintenance costs. Furthermore, sincethe pipetting modules can be made small and compact in design, deadvolumes between pump(s) and pipetting tips can be made small whichadvantageously enables high-precision pipetting of fluids.

According to a preferred embodiment of the pipetting device, thepipetting module is provided with a pump connected to the pipetting tipby means of the pump conduit to thereby obtain a highly-integratedpipetting device.

According to another preferred embodiment of the pipetting device, thepump conduit of the at least one pipetting module is fluidicallyconnected to a liquid system fluid reservoir to at least partly fill thepump conduit with liquid system fluid which can either be transportedtowards the liquid system fluid reservoir to aspirate fluids into thefluid sample conduit or transported towards the pipetting tip todispense fluids from the fluid sample conduit, regularly with a gasbubble in-between the (non-pipetted) liquid system fluid and the(pipetted) fluid samples.

The use of a liquid system fluid advantageously allows forhigh-precision pipetting of fluids due to a reduced compressibility ofthe liquid system fluid and lower temperature-induced variationscompared to the otherwise purely gaseous system fluid.

When using liquid system fluid, it is highly preferred to use a pump ofthe rotary displacement pump type such as a gearwheel pump forgenerating positive or negative pressure to be transferred to thepipetting tip. While being comparably low in weight, a gearwheel pumpadvantageously allows for a definite transport of the liquid systemfluid thus enabling very precise pipetting of fluids. Furthermore, agearwheel pump enables pipetting of a wide range of volumes, so that asame pump may be used for both pipetting of fluid samples and pipettingof (the much higher volumes of) wash fluids in order to wash the fluidsample conduit. Otherwise, a gearwheel pump may be integrated into thepipetting module. The use of a gearwheel pump thus advantageouslyenables the pipetting device to have a reduced complexity as, forinstance, reflected by avoiding usage of various pumps and tubing andsaving constructional space.

In case fluids aspirated into the fluid sample conduit containmicroscopic (solid) particles such as magnetic beads, which, forexample, are being used in various nucleic acids separation techniques,is has been shown that such particles are very likely to be mixed withthe liquid system fluid and may even get into the pump to cause severedamage due to an increased abrasion especially in case of usinggearwheel pumps.

In order to overcome such a problem, it is preferred to arrange thefluid sample conduit for receiving the fluid samples aspirated throughthe pipetting tip in at least approximately vertical orientation withrespect to gravity so that the fluid sample conduit extends along thedirection of fall. Hence, providing for a vertically oriented fluidsample conduit, the solid particles contained therein may advantageouslybe made to drop down by the pure action of gravity which advantageouslyavoids the particles to be mixed with the liquid system fluid.

In order to overcome the problem of solid particles entering the liquidsystem fluid and in particular entering the gearwheel pump it ispreferred that fluids containing such particles are only aspirated intothe fluid sample conduit of the pipetting module but not beyond. Thismeans that in a pipetting process the process is controlled to aspiratea volume of a particle containing fluid which is smaller than the volumeof the fluid sample conduit of the pipetting module. Specifically, inthe case of a pump conduit having plural windings including linearlyextending portions connected by curved portions, as above-detailed, thefluid is only aspirated into the linearly extending portion directlyconnected (i.e. adjacent) to the pipetting tip but not in the curvedportion directly connected (i.e. adjacent) to this linearly extendingportion.

In the pipetting device according to an embodiment of the invention,each pipetting module may further include one or more sensors, adaptedfor sensing of physical parameters, e.g. flow rate and liquid pressurein the fluid sample conduit, in particular, when pipetting operationsare being performed, or for sensing of a distance between the pipettingtip and another object such as a work-surface. For instance in the caseof a pump conduit having plural windings including linearly extendingportions connected by curved portions, as above-detailed, the pipettingmodule may include a sensor for detecting a boundary between liquid andgas or between two types of liquid so as to avoid aspirating fluidsbeyond the fluid sample conduit.

According to yet another preferred embodiment of the pipetting device,the at least one pipetting module has a housing at least partlyaccommodating the pump conduit which allows for a quick fixing orremoving, in particular replacing, of the pipetting module. In case ofusing liquid system fluid, it may be preferable that an outer conduitdisposed outside the housing be exclusively filled with liquid systemfluid. It may also be preferred to provide the housing with at least oneconnector selected from the group consisting of a fluidic connector andan electric connector enabling a highly-compact and flexible design ofthe pipetting module.

In yet another preferred embodiment of the invention, the pipettingdevice is being provided with a plurality of pipetting modules, eachbeing detachably fixed to the automated positioning device. In that, thepipetting modules may be serially aligned with respect to each other,wherein a distance in-between adjacent pipetting tips is being adaptedto correspond to a distance in-between adjacent cavities used forpipetting of fluid samples. Hence, the pipetting device mayadvantageously be used for pipetting of fluids contained inequally-distanced cavities, such as wells of multi-well plates.

According to another embodiment of the invention, a modular pipettingunit for detachably attaching to an automated positioning device of apipetting device for pipetting of fluid samples is provided. The modularpipetting unit includes at least one pipetting tip for pipetting fluidsamples and a pump conduit for transferring a negative or positivepressure to the pipetting tip, wherein the pipetting tip and at least aportion of the pump conduit adjoining the pipetting tip mutually definea fluid sample conduit for receiving the fluid samples.

According to another embodiment of the invention, a method for pipettingof fluid samples using a pipetting device is provided. The pipettingdevice for use with the method comprises at least one (e.g. modular)pipetting unit including a pipetting tip for pipetting of fluid samplesand a pump conduit for transferring a negative or positive pressure tothe pipetting tip, wherein the pipetting tip and at least a portion ofthe pump conduit adjoining the pipetting tip mutually define a fluidsample conduit for receiving the fluid samples. In the method of theinvention, pipetting of fluid samples is performed in such a manner thata pipetted volume of a fluid sample that contains solid particles issmaller than a volume of the fluid sample conduit. More preferably, eachvolume of pipetted fluid sample is smaller than a volume of the fluidsample conduit. Further in a preferred method of the invention thepipetting processes are controlled so that sample fluid does not leavethe pipetting module in direction of the system fluid reservoir.

According to another embodiment of the invention, a pipetting system isprovided. The pipetting system comprises at least one pipetting unitincluding a pipetting tip for pipetting of fluid samples and a pumpconduit for transferring a negative or positive pressure to thepipetting tip, wherein the pipetting tip and at least a portion of thepump conduit adjoining the pipetting tip mutually define a fluid sampleconduit for receiving the fluid samples. The fluid sample conduit mostpreferably is at least approximately vertically aligned. It furthercomprises an automated positioning device for positioning of the atleast one pipetting unit and a controller for controlling of pipettingof fluid samples. In the system of the invention, the controller isconfigured to control pipetting of fluid samples in such a manner thateach pipetted volume of the fluid samples is smaller than a volume ofthe fluid sample conduit.

According to a preferred embodiment of the system, the pipetting unit isa modular pipetting unit (pipetting module) being detachably fixed tothe automated positioning device. In that case it may be highlypreferred to have a pump accommodated in the modular pipetting unitwhich is being connected to the pipetting tip by means of the pumpconduit.

The above embodiments of the present invention will now be described ingreater detail below with reference to the accompanying drawings, wherelike designations denote like or similar elements.

Referring to FIG. 1, an exemplary embodiment of the modular pipettingunit (pipetting module) according to the invention is explained.Accordingly, a pipetting module 2 (modular pipetting unit) includes are-usable pipetting tip 3 (needle) for pipetting of fluid samples whichis fixed to an elongated hollow cartridge 7 (housing) by means of athreaded connection. The threaded connection is comprised of a threadedpin screwed into a threaded hole of the cartridge 7 (not furtherdetailed in FIG. 1). A corrugated outer surface 9 at the cartridge7-sided end of the pipetting tip 3 facilitates turning of the pipettingtip 3 for screwing or unscrewing with cartridge 7. The pipetting tip 3may thus be readily fixed or removed and replaced by another pipettingtip 3 as desired.

The pipetting tip 3 which is made of metallic material (e.g. steel) isfluidically connected to a plastic-made flexible pump conduit 4accommodated in a cavity 12 of the cartridge 7 for transferring apump-generated negative or positive pressure to the pipetting tip 3. Thecavity 12 of the cartridge 7 is provided with a plurality of guidingfaces 6 arranged along an inner wall 8 of cartridge 7 for guiding thepump conduit 4. Supported by the guiding faces 6, the pump conduit 4winds three and a half times along the inner wall 8 of housing 7 to befinally connected with a fluidic connector 10.

Due to a nearly rectangular (parallel-epipedic) shape of the cavity 12,the pump conduit 4 has longer (linearly extending) conduit portions 22in a first direction and shorter (linearly extending) conduit portions23 in a second direction vertically aligned to the first direction,which are connected by curved conduit portions 24. When orienting theelongated cartridge 7 in vertical direction with respect to gravity, thelonger conduit portions 22 extend in vertical direction.

Specifically, the pump conduit 4 includes a first longer portion 5which, being linearly aligned with the pipetting tip 3, extends from thepipetting tip 3 to the beginning of the first curved conduit portion 11of the pump conduit 4. The first longer portion 5 of the pump conduit 4and the pipetting tip 3 may mutually define a fluid sample conduit 25for receiving fluid samples aspirated through the pipetting tip 3. Whenvertically orienting the elongated cartridge 7 (i.e. verticallyorienting the pipetting tip 3), the fluid sample conduit 25 extends inthe direction of fall.

When using liquid system fluid, the vertically oriented fluid sampleconduit 25 causes microscopic (solid) particles such as magnetic beadscontained in fluid samples to drop down by the pure action of gravitywhich advantageously avoids diffusing the particles into the liquidsystem fluid. For this reason fluid samples containing microscopicparticles preferably are only aspirated into this vertically orientedfluid sample conduit 25 but not beyond, i.e., such fluid samples are notaspirated into the first curved conduit portion 11. Otherwise, fluidsamples free of microscopic particles can also be aspirated beyond thefirst lower portion 5 of the pump conduit 4. In the latter case, one ormore longer conduit portions 22, one or more shorter conduit portions23, one or more curved conduit portions 24 and the pipetting tip 3 maymutually define a fluid sample conduit.

A pipetting unit with such an internal fluid sample conduit 25 has asignificant advantage. When pipetting is controlled in a way that otherfluids than system fluid are only aspirated into this fluid sampleconduit 25 this will be the only place where contamination can occur. Inpractice substances as e.g. proteins contained in sample fluids areadsorbed on the inner walls of the conduit. During subsequent pipettingprocesses such adsorbed substances are partially desorbed andcontaminate dispensed fluids. In practice contaminated tubings have tobe replaced after some month, the time very much depending on the typeof sample fluids and intensity of usage. Replacement of the tubings canbe quite cumbersome and often needs a service technician. Due to themodular pipetting unit of the present invention this service action canbe simplified very much because the only item to be exchanged is thedetachable pipetting unit which incorporates the tubing to be exchanged.

Further modular pipetting units are advantageous which have at least onewinding of the pump conduit inside the pipetting unit. By this thevolume capacity of the pipetting unit is increased and pipettingprocesses are not so restricted by the requirement that fluid samplesare only aspirated into the pipetting unit but not beyond.

Having a fluid conduit inside the housing of the modular pipetting unitfurther has the advantage that the conduits are protected againstmechanical stress and ultraviolet radiation. Further a metal housingprovides protection against electromagnetic radiation so that detectionsof e.g. phase boundaries, liquid level detection are not disturbed.

In order to enable pipetting of sufficiently large volumes of fluidsamples, the first longer portion 5 of the pump conduit 4 preferably hasa length of more than 5 cm and may, e.g., have a length in a range offrom 5 to 25 cm to achieve sufficiently strong inhibition of particlediffusion. Furthermore, the first longer portion 5 of the pump conduit 4preferably has a diameter of less than 3 mm.

The pipetting module 2 further includes a sensor arrangement 13comprising plural sensors electrically connected to a controller (notillustrated) for controlling of pipetting operations. The pipettingmodule 2 is provided with an electric connector 14 to be connected withelectric lines for connecting the pipetting module 2 with thecontroller. Sensors of the sensor arrangement 13 are being adapted forsensing of physical parameters, in particular during pipetting offluids, such as fluid flow rate and fluid pressure in the fluid sampleconduit 25, or a distance between the pipetting tip 3 and another objectsuch as a work-surface. Further such sensor can be a sensor fordetecting a boundary between liquid and gas or between two types ofliquid. This enables to either control and/or monitor pipettingprocesses based on the sensor signals. E.g. it can be avoided toaspirate fluid samples beyond the sample fluid conduit by monitoringclose to the upper end of the sample fluid conduit that no gas/liquid orliquid/liquid boundary passes by during an aspiration. Suitable sensorscan be e.g. optical sensors or inductive sensors which detect changes ofoptical properties or of inductance at phase boundaries.

In FIG. 1, the cartridge 7 is shown without side walls for the purposeof illustration only. Stated more particularly, the cartridge 7 is aclosed housing aside from the screwed hole for fixing the pipetting tip3 and the fluidic connector 10.

Referring to FIG. 2, an exemplary embodiment of the pipetting device 1according to the invention is explained. The pipetting device 1 includesa plurality of pipetting modules 2 as illustrated in FIG. 1.Accordingly, each of the pipetting modules 2 includes a pipetting tip 3which is fixed to cartridge 7 and connected to the pump conduit 4accommodated therein. While a number of four pipetting modules 2 areillustrated in FIG. 2, it, however, is to be understood that more orless pipetting modules 2 can be used in accordance with specific demandsfor the pipetting of fluid samples.

The pipetting device 1 includes an automated positioning device 26 whichcan be used to transfer the pipetting tips 3 with respect to cavitiescontaining the fluid samples to be transferred. Each pipetting module 2is detachably mounted to a transfer head 15, which can be slidably movedin vertical direction along vertically extending vertical guiding rails19, e.g., by means of a spindle drive. The vertical guiding rails 19 forguiding the transfer head 15 are fixed to a sliding carriage 20 whichcan be moved in two directions of travel in a horizontal plane using atwo-rail translation system comprising two rails arranged in orthogonalrelationship with respect to each other for moving the transfer head 15.In FIG. 2, one horizontal guiding rail 16 is illustrated. Since suchpositioning system is well-known to those of skill in the art, it is notfurther detailed herein.

Each pipetting module 2 is vertically oriented with respect to gravitywhich results in vertically oriented fluid sample conduits 25 foraccommodating fluid samples aspired through the pipetting tips 3, sothat microscopic particles contained in the fluid samples are caused todrop down by the action of gravity.

In the pipetting device 1, the fluidic connector 10 of each of thepipetting modules 2 is fluidically connected to a micro-gearwheel pump18 by the pump conduit 4, which is guided by a separate metallic guidingchain 17 comprised of plural chain links 21 to mechanically protect thepump conduit 4. Each gearwheel pump 18 is fixed to the sliding carriage20 and thus moves together with the sliding carriage 20 in a horizontalplane. Alternatively, the micro-gearwheel pumps 18 might be fixed to thetransfer head 15. Each gearwheel pump 18 is fluidically connected to asystem fluid reservoir 32 by means of a reservoir tubing 29(schematically illustrated in FIG. 4).

As illustrated in FIG. 2, in the pipetting device 1, the pipettingmodules 2 are serially aligned with respect to each other, wherein adistance in-between adjacent pipetting tips 3 is chosen to correspond toa distance in-between adjacent cavities of a plurality ofequally-distanced cavities containing the fluid samples to betransferred. The pipetting device 1 of FIG. 2 may thus advantageously beused for pipetting of fluid samples contained in equally-distancedcavities, such as multi-well plates.

Reference is now made to FIG. 3 illustrating a variant of the pipettingdevice of FIG. 2. In order to avoid unnecessary repetitions onlydifferences with respect to FIG. 2 are explained and otherwise referenceis made to explanations made in connection with FIG. 2. In the pipettingdevice of FIG. 3, each pipetting module 2 accommodates a micro-gearwheelpump 18 which is fluidically connected to the pump conduit 4 forgenerating a positive or negative pressure in the pipetting tips 3. Eachgearwheel pump 18 accommodated in the cartridge 7 is fluidicallyconnected to a system fluid reservoir 32 by means of a reservoir tubing29 (schematically illustrated in FIG. 4). In that, the reservoir tubing29 of each of the pipetting modules 2 is at least partly guided by aseparate metallic guiding chain 17 to provide for mechanical protection.Said guiding chain 17 having a number of rigid chain elements which arefixed to each other in a way which allows relative movement in onedirection. The chain elements each having a channel. The channels of thechain elements being aligned in a way to provide a channel in which thereservoir tubing 29 is housed and by that sheltered as well as able tofollow the up- and down movements of the respective pipetting module.

In FIG. 3, a DC electric motor 33 for vertically driving the transferhead 15 is depicted. Each pipetting module 2 of the pipetting device 1of FIG. 3 having an integrated micro-gearwheel pump 18 thusadvantageously allows for a reduced complexity of the pipetting device 1to thereby save constructional space and costs and facilitatemaintenance operations.

Reference is now made to FIG. 4 illustrating a schematic diagram of apipetting channel 27 including a pipetting module 2 of the pipettingdevice 1 of FIG. 2 or FIG. 3 used for pipetting of fluid samples. Thepipetting channel 27 is a functional entity for pipetting of fluidsincluding an individual pipetting module 2. Due to four pipettingmodules 2, the pipetting device 1 has a number of four identicalpipetting channels 27, each of which including an individual pipettingmodule 2.

Accordingly, an individual pipetting channel 27 of the pipetting device1 including an individual pipetting module 2 comprises:

-   -   the pipetting tip 3 of the pipetting module 2;    -   the pump conduit 4 connecting the pipetting tip 3 with a first        inlet/outlet port 34 of the gearwheel pump 18; and    -   a reservoir tubing 29 connecting a second inlet/outlet port 35        of the gearwheel pump 18 with a system fluid reservoir 32.

The pump conduit 4 is provided with an optical flow sensor 28 used forsensing of fluid flows in the fluid sample conduit 25 which is part ofthe sensor arrangement 13. Further, the reservoir tubing 29 passesthrough system fluid valve 31, adapted for opening/closing reservoirtubing 29, and is provided with a pressure sensor 30 for sensing ofsystem fluid pressure in reservoir tubing 29.

The gearwheel pump 18 for generating a positive or negative pressure inthe pipetting tip 3 of each of the pipetting channels 27 is connected tothe liquid system fluid reservoir 32 for at least partly filling thereservoir tubing 29 or for (completely) filling the reservoir tubing 29and at least partly filling the pump conduit 4 (at least except for thefluid sample conduit 25) of the pipetting channel 27 with liquid systemfluid. In case the micro-gearwheel pump 18 is located outside thecartridge 7, it can be preferred to exclusively fill the reservoirtubing 29 and those parts of the pump conduits 4 which are locatedoutside the cartridge 7 with liquid system fluid.

In case the gearwheel pump 18 is accommodated in the cavity 12 of thecartridge 7 of the pipetting module 2 to which it belongs, each of thepipetting channels 27 is a structural entity as identified by thepipetting module 2. In other words, each of the pipetting modules 2 mayinclude all components of a pipetting channel 27 as illustrated in FIG.3.

Reference is now made to FIGS. 5A-5D illustrating cross-sectional viewsof the micro-gearwheel pump 18 of the pipetting device 1 of FIG. 2 andFIG. 3. The micro-gearwheel pump 18 includes an inner rotor (externallytoothed inner gearwheel) 36 turning around an inner rotor rotation axis38 and an outer rotor (internally toothed outer gearwheel) 37 turningaround an outer rotor rotation axis 39, with both axes 38, 39 beingoffset with respect to each other. The inner and outer rotors 36, 37 arein meshing engagement to thereby circumferentially form pressurechambers 40 cyclically changing their sizes and positions when rotatingthe inner rotor 36 with respect to the outer rotor 37. The pressurechambers are connected to the first and second inlet/outlet ports 34, 35to generate low-pulsation flows of liquid system fluid between the portswhen increasing the pressure chambers 40 at the aspirating port anddecreasing the pressure chambers 40 at the dispensing port. Thedirection of flow can be reversed in changing the driving direction ofthe micro-gearwheel pump 18.

In FIGS. 5A-5D, four consecutive positions of the inner rotor 36 withrespect to the outer rotor 37 are depicted illustrating transport offluid from the first inlet/outlet port 34 (aspirating port) to thesecond inlet/outlet port 35 (dispensing port) in turning the inner rotor36 in clockwise direction.

Accordingly, generating a liquid system fluid flow directed to thesystem fluid reservoir 32 (system fluid reservoir 32 is connected to thedispensing port of the micro-gearwheel pump 18) generates a negativepressure in the pipetting tip 3 to thereby aspire fluid into the fluidsample conduit 25. On the other hand, generating a liquid system fluidflow directed to the pipetting tip 3 (pipetting tip 3 is connected tothe dispensing port of the micro-gearwheel pump 18) generates a positivepressure in the pipetting tip 3 to thereby dispense fluid contained inthe fluid sample conduit 25.

The system fluid valve 31 is operatively coupled to the micro-gearwheel18 and is opened when a pumping operation of the micro-gearwheel pump 18is performed to enable liquid system fluid flow through the reservoirtubing 29 and is closed when the micro-gearwheel pump 18 is not operatedto close the reservoir tubing 29. Pressure sensor 30 is used for sensingof system fluid pressure in reservoir tubing 29.

The micro-gearwheel pump 18 may, e.g., be used for pipetting of fluidsample volumes in a range of from 10 μl to 1500 μl. Moreover, it may,e.g., be used for pipetting of fluid samples having flow rates in arange of from 1200 μl/sec to 72 ml/sec. Based upon such a wide range offlow rates, the micro-gearwheel pump 18 may also be used for washing thepipetting tips 3, for instance, in dispensing liquid system fluidthrough the pipetting tips 3.

While, in above embodiments, the pipetting modules 2 have been showneach to be connected to a separate micro-gearwheel pump 18, inparticular in case of locating the micro-gearwheel pump 18 outside thepipetting module 2, it may be preferable to connect the pipettingmodules 2 to a single common gearwheel pump 18.

While the pipetting modules 2 have been shown to be mounted to a sametransfer head 15 in above embodiment, it may be preferable to mount eachof the pipetting modules 2 to a separate transfer head 15 toindependently move the pipetting tips 3.

The pipetting device 1 further includes a controller 41 for controllingof pipetting of fluids of each of the pipetting channels 27. In that,the controller is being configured to control pipetting of each of thepipetting channels 27 in such a way that each pipetted volume of fluidsis smaller than a volume of the fluid sample conduit 25 of the pipettingmodule 2 concerned.

Accordingly, by the above discussion a pipetting device 1 has beendisclosed which comprises at least one modular pipetting unit 2including a pipetting tip 3 for pipetting of fluid samples and a pumpconduit 4 for transferring a negative or positive pressure to thepipetting tip 3, wherein the pipetting tip 3 and at least a portion 5 ofthe pump conduit 4 adjoining the pipetting tip 3 mutually define a fluidsample conduit 25 for receiving the fluid samples, and wherein themodular pipetting unit 2 being detachably attached to an automatedpositioning device 26 for positioning the modular pipetting unit 2.

In another embodiment, the modular pipetting unit 2 has an integratedpump 18 connected to the pipetting tip 3 by means of the pump conduit 4.

In another embodiment, the pump is a pump of the rotary displacementpump type such as a gearwheel pump 18.

In another embodiment, the pump conduit 4 is being at least partlyfilled with a liquid system fluid.

In another embodiment, the fluid sample conduit 25 has an at leastapproximate vertical orientation with respect to gravity.

In another embodiment, the modular pipetting unit 2 comprises at leastone sensor 13 adapted for sensing of physical parameters.

In another embodiment, the modular pipetting unit 2 includes a housing 7at least partly accommodating the pump conduit 4.

In another embodiment, the housing 7 is provided with at least oneconnector selected from the group consisting of a fluidic connector 10and an electric connector 14.

In another embodiment, the automated positioning device 26 comprisescomponents of movement in two directions of travel in a plane and athird direction of travel vertical thereto, wherein the modularpipetting unit 2 is detachably attached to a transfer head 15 moveablealong the third direction.

In another embodiment, the pipetting device 1 comprises a plurality ofmodular pipetting units 2 having a plurality of equally-distancedpipetting tips 3, wherein a distance in-between adjacent pipetting tips3 corresponds to a distance in-between adjacent cavities used forpipetting of the fluid samples.

In another embodiment, a modular pipetting unit 2 comprises at least onepipetting tip 3 for pipetting of fluid samples and a pump conduit 4 fortransferring a negative or positive pressure to the pipetting tip 3,wherein the pipetting tip 3 and at least a portion 5 of the pump conduit4 adjoining the pipetting tip 3 mutually define a fluid sample conduit25 for accommodating the fluid samples.

In still another embodiment, a method for pipetting of fluid samples hasbeen disclosed and comprises using a pipetting device 1 comprising atleast one pipetting unit 2 provided with a pipetting tip 3 for pipettingof fluid samples and a pump conduit 4 for transferring a negative orpositive pressure to the pipetting tip 3, wherein the pipetting tip 3and at least a portion 5 of the pump conduit adjoining the pipetting tipmutually define a fluid sample conduit 25 for receiving the fluidsamples, wherein pipetting of the fluid samples is performed in such away that a pipetted fluid sample volume is smaller than a volume of thefluid sample conduit 25.

In yet another embodiment, a pipetting system has been disclosed andcomprises at least one pipetting unit 2 which includes a pipetting tip 3for pipetting fluid samples and a pump conduit 4 for transferring anegative or positive pressure to the pipetting tip 3, wherein thepipetting tip 3 and at least a portion 5 of the pump conduit adjoiningthe pipetting tip 3 mutually define a fluid sample conduit 25 forreceiving the fluid samples; an automated positioning device 26 forpositioning of the at least one pipetting unit 2; and a controller 41for controlling of pipetting of the fluid samples, configured to controlpipetting of fluids such that each pipetted volume of the fluid samplesis smaller than a volume of the fluid sample conduit.

In another embodiment and in the pipetting system, the pipetting unit 2is a modular pipetting unit being detachably attached to the automatedpositioning device.

In another embodiment and in the pipetting system, the modular pipettingunit 2 accommodates a pump 18 connected to the pipetting tip 3 by meansof the pump conduit 4.

Obviously many modifications and variations of the present invention arepossible in light of the above description. It is therefore to beunderstood, that within the scope of appended claims, the invention maybe practiced otherwise than as specifically devised.

1. A pipetting device for an automated positioning device, comprising:at least one modular pipetting unit which includes a pipetting tip forpipetting of fluid samples; and a pump conduit for transferring anegative or positive pressure to said pipetting tip, wherein saidpipetting tip and at least a portion of said pump conduit adjoining saidpipetting tip mutually define a fluid sample conduit receiving saidfluid samples, and wherein said modular pipetting unit is detachablyattachable to the automated positioning device which positions saidmodular pipetting unit.
 2. The pipetting device according to claim 1,wherein said modular pipetting unit has an integrated pump connected tosaid pipetting tip by means of said pump conduit.
 3. The pipettingdevice according to claim 2, wherein said pump is a pump of the rotarydisplacement pump type such as a gearwheel pump.
 4. The pipetting deviceaccording to claim 1, wherein said pump conduit is at least partlyfilled with a liquid system fluid.
 5. The pipetting device according toclaim 1, wherein said fluid sample conduit has an at least approximatevertical orientation with respect to gravity.
 6. The pipetting deviceaccording to claim 1, wherein said modular pipetting unit comprises atleast one sensor for sensing of physical parameters.
 7. The pipettingdevice according to claim 1, wherein said modular pipetting unitincludes a housing at least partly accommodating said pump conduit. 8.The pipetting device according to claim 7, wherein said housing isprovided with at least one connector selected from the group consistingof a fluidic connector and an electric connector.
 9. The pipettingdevice according to claim 1, wherein said modular pipetting unit isdetachably attachable to a transfer head of the automated positioningdevice.
 10. The pipetting device according to claim 1, comprising aplurality of modular pipetting units having a plurality ofequally-distanced pipetting tips, wherein a distance in-between adjacentpipetting tips corresponds to a distance in-between adjacent cavitiesused for pipetting of said fluid samples.
 11. A modular pipetting unitcomprising: at least one pipetting tip for pipetting of fluid samples;and a pump conduit for transferring a negative or positive pressure tosaid pipetting tip, wherein said pipetting tip and at least a portion ofsaid pump conduit adjoining said pipetting tip mutually define a fluidsample conduit for accommodating said fluid samples.
 12. A method forpipetting of fluid samples, comprising: providing a pipetting devicewhich comprises at least one pipetting unit provided with a pipettingtip for pipetting of fluid samples and a pump conduit, said pipettingtip and at least a portion of said pump conduit adjoining said pipettingtip mutually define a fluid sample conduit, and said pump conduit beingat least partly filled with a liquid system fluid; and moving saidliquid system fluid in said pump conduit to transfer a negative orpositive pressure to said pipetting tip via said fluid sample conduit topipette said fluid samples, wherein a pipetted fluid sample volume issmaller than a volume of said fluid sample conduit.
 13. A pipettingsystem, comprising: at least one pipetting unit which includes apipetting tip for pipetting fluid samples and a pump conduit fortransferring a negative or positive pressure to said pipetting tip,wherein said pipetting tip and at least a portion of said pump conduitadjoining said pipetting tip mutually define a fluid sample conduit forreceiving said fluid samples; an automated positioning device forpositioning of the at least one pipetting unit; and a controller forcontrolling pipetting of said fluid samples such that each pipettedvolume of the fluid samples is smaller than a volume of said fluidsample conduit.
 14. The pipetting system according to claim 13, whereinsaid pipetting unit is a modular pipetting unit being detachablyattached to said automated positioning device.
 15. The pipetting systemaccording to claim 14, wherein said modular pipetting unit accommodatesa pump connected to said pipetting tip by said pump conduit.
 16. Thepipetting system according to claim 13, wherein said pump conduit is atleast partly filled with a liquid system fluid.
 17. The pipetting systemaccording to claim 13, wherein said fluid sample conduit has an at leastapproximate vertical orientation with respect to gravity.
 18. Thepipetting system according to claim 13, wherein said pipetting unitcomprises at least one sensor for sensing of physical parameters. 19.The pipetting system according to claim 13, wherein said pipetting unitincludes a housing at least partly accommodating said pump conduit, andsaid housing is provided with at least one connector selected from thegroup consisting of a fluidic connector and an electric connector. 20.The pipetting system according to claim 13, wherein said automatedpositioning device comprises components of movement in two directions oftravel in a plane and a third direction of travel vertical thereto,wherein said pipetting unit is detachably attached to a transfer headmoveable along the third direction.